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Nevirapine versus efavirenz in 742 patients: no link of liver toxicity with female sex, and a baseline CD4 cell count greater than 250 cells/μl
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[Research Letters]
AIDS: Volume 20(17) 14 November 2006 p 2233-2236
Manfredi, Roberto; Calza, Leonardo
Department of Clinical and Experimental Medicine, Division of Infectious Diseases, 'Alma Mater Studiorum' University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
Abstract
Recent studies have reported increased nevirapine hepatotoxicity in female patients with CD4 lymphocyte counts greater than 250 cells/μl (especially pregnant women). However, our open-label comparison of 742 patients treated with either nevirapine or efavirenz-based HAART as naive patients, experienced subjects, or patients on salvage therapy, found no increased hepatotoxicity in nevirapine-treated subjects, in particular with regard to both sex (females versus males) and T-cell-mediated immunodeficiency (CD4 cell counts above versus below 250 cells/μl).
A broad spectrum of mechanisms may sustain HAART hepatotoxicity. Non-nucleoside reverse transcriptase inhibitors (NNRTI) is an easy class to explore, because it includes two major compounds (nevirapine and efavirenz) that share genotypic crossreaction, so that a previous failure with one component precludes the use of the second derivative [1]. Although several studies have not shown remarkable differences in major efficacy parameters compared with efavirenz [2-5], since 2002 efavirenz has retained its recommendation in antiretroviral-naive patients as a result of its superior intrinsic activity [1,3,4], whereas nevirapine is often suggested as a part of switch, simplification, or de-intensification regimens in patients who have achieved sustained viral suppression and complete immune reconstitution [1], but have suffered from adverse events or excessive pill burden [1,3,6-8], as well as a component of rescue treatments [3]. All these issues, together with convenient administration and a favourable pharmacoeconomic profile (as represented by a 57.12% lower cost compared with efavirenz, and even more difference compared with protease inhibitors) [9], are valid reasons for the continued, extensive use of nevirapine in daily clinical practice, just when a retrieved immune recovery is almost the rule, and the female sex is increasingly represented in treated HIV-infected patients [3,8]. Since early 2005 some reports conducted on limited patient series showed increased hepatotoxicity in pregnant women with CD4 cell counts greater than 250 cells/μl. Such reports were accompanied by a specific US Food and Drug Administration advisory issued in January 2005 [10], which underlined and apparently enlarged '... warnings against ongoing nevirapine treatment in women with a CD4 count over 250, due to a greatly increased risk of serious liver toxicity. The warnings do not apply to single-dose nevirapine, which does not cause this problem'. This last statement does not seem to be well substantiated, because most studies were conducted on pregnant women [11,12] (whereas the advisory included all women, regardless of pregnancy) [10]. It was stated that single-dose nevirapine was less toxic than twice daily administration, whereas the large 2NN study demonstrated a slightly increased toxicity just for once-daily administration [2], other non-comparative surveys failed in obtaining reduced hepatotoxicity with once-daily nevirapine [4]. A very recent Cochrane review showed a possible increased toxicity with once-daily nevirapine [5], and pharmacokinetic studies also demonstrated greater Cmin/Cmax nevirapine levels during once daily administration [13]. A large retrospective study in 2006, conducted on 197 pregnant women exposed to nevirapine for 7 days or longer, demonstrated a 5.6% overall toxicity rate, no fatalities, and especially no serious hepatotoxicity, except one case of grade 4 cholestasis (attributable to underlying conditions) [14]. In the meantime, some authors detected unpredictable serum nevirapine concentrations, which could be responsible for adverse events (including hepatotoxicity) in selected patients [13,15].
In our open-label experience, conducted in over 1000 patients treated with HAART for 12 months or longer, the hepatotoxicity pattern of both NNRTI was assessed on the basis of three different backgrounds (as previously described) [7,16]: antiretroviral-naive patients, starting NNRTI-based HAART; subjects experienced with two to 10 therapeutic lines (but still NNRTI naive); and patients who added an NNRTI only on late rescue therapies containing four or more different anti-HIV drugs (and always including at least one protease inhibitor). Only patients with nevirapine administered at a dose of 200 mg twice a day were considered. Of 846 overall patients matching these characteristics, 64 were excluded as a result of less than 90% adherence levels (as assessed by patients' declarations and direct drug distribution accountability at our centre), 31 were excluded because of subsequent efavirenz-nevirapine use, and nine patients were excluded because they took once-daily nevirapine. Pregnant patients were not admitted to the present study, because the use of efavirenz is not allowed. Of 742 evaluable subjects, 346 consecutive patients treated with nevirapine were compared with 396 patients who took efavirenz, by a 12-36-month univariate-multivariate analysis of serum liver abnormalities, on the grounds of a spectrum of epidemiological, clinical, and laboratory parameters. Instead of normal laboratory levels, we referred to the baseline value of each enrolled patient. The two study groups were comparable with regard to the main demographic-epidemiological features and clinical stage of HIV disease, whereas a lower CD4 lymphocyte count was found in patients who started efavirenz (P < 0.00001), as well as greater HIV viraemia (P < 0.001). The last difference concerned only the 93 antiretroviral-naive patients. Moreover, no differences occurred as to the type-duration of eventual previous anti-HIV therapy, the frequency-length of treatment with protease inhibitors or antitubercular therapy, eventual co-infection with hepatitis C/B/D viruses, or other chronic hepatobiliary-pancreatic disorders (biliary gallstones, cholecystitis, pancreatitis), and alcohol-drug abuse or methadone administration. A twofold or greater increase in serum transaminase levels compared with baseline was significantly linked to the use of nevirapine compared with efavirenz (P < 0.00001). The time to peak transaminase alterations was shorter in the nevirapine group (P < 0.00001), and hepatotoxicity represented the main determinant of discontinuation in 20 nevirapine patients, compared with five efavirenz subjects (P < 0.001; Table 1). More frequent alterations were also detected for serum bilirubin (P = 0.05), gamma glutamyl transferase (P < 0.0004), alkaline phosphatase (P = 0.003), and albumin levels (P = 0.05) in the nevirapine compared with the efavirenz group (data not shown). All differences were carefully controlled for each available variable: a link between the frequency of hepatotoxicity, time to peak transaminases, and NNRTI withdrawal was disclosed for concurrent hepatitis C/B/D virus infection plus chronic hepatobiliary-pancreatic disorders only at logistic regression multivariate analysis (P < 0.03). In particular, when stratifying patients by sex and an initial CD4 cell count greater than 250 cells/μl, no significant difference emerged among patients taking either nevirapine or efavirenz, even after controlling for all other variables. Finally, no differences were found when analysing the three patient groups at enrolment (the 93 antiretroviral-naive subjects, the 503 subjects treated with two to 10 lines, and the 146 patients on four or more drugs, but NNRTI naive, data not shown).
Nevirapine-containing HAART remains more hepatotoxic than efavirenz-based regimens [6,7,16], and a key role may be played by underlying chronic viral hepatitis and hepatobiliary-pancreatic disorders, as previously demonstrated [17]. As demonstrated in our study conducted on 742 patients who received an NNRTI for the first time in different baseline conditions, female sex and a CD4 lymphocyte count greater than 250 cells/μl do not prompt any adjunctive risk of hepatotoxicity. In the meantime, recent studies have also underlined the long-term efficacy-safety profile of nevirapine [4,8]. In a multicentre experience that recruited 613 patients treated with nevirapine for 2 years or more (median follow-up 43 months) [4], fivefold or greater increases in transaminase levels were observed in less than 2% of cases, whereas viral suppression was achieved in approximately 75% of patients (including naive patients, failing subjects, and those switching for toxicity). In their 2006 Cochrane revision, Siegfried et al. [5] assessed nevirapine-based regimens as providing favourable efficacy and durability, associated with a low adverse event profile and potential for drug-drug interactions. In both published series [4,5], approximately 40% of patients were women, and no significant difference with regard to toxicity or efficacy was found compared with efavirenz-treated patients [5].
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